Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts

Abstract

It has been suggested that cytomegalovirus (CMV) infection is involved in allograft rejection. In liver transplantation, it has been suggested that CMV is associated with the development of vanishing bile duct syndrome (VBDS), and persistent CMV has been found in liver grafts that develop chronic rejection. In this experimental study, the effect of rat CMV (RCMV) infection on intragraft changes was investigated in a rat model of acute liver allograft rejection. Liver transplantations were performed in a rat strain combination of PVG (RT1 c ) = BN (RT1 n ). No immunosuppression was given. One group of animals was infected with RCMV Maastricht Strain (10 5 plaque-forming units, intraperitoneally), and another group was left uninfected. The grafts were examined histologically after the rats were killed on postoperative days 7 through 9 at the early phase and days 20 through 30 at the late phase of rejection. Immunohistochemical studies were performed to demonstrate the immunological activation markers major histocompatibility complex class II and interleukin 2 receptors, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and their ligands. RCMV infection was demonstrated from the grafts by culture and direct antigen detection. In liver allografts undergoing acute rejection, CMV significantly increased portal inflammation and caused more severe bile duct damage than in the uninfected grafts. CMV was also linked to the induction of VCAM-1 in the endothelial cells. The ongoing infection was found to vary over time in the different structures of the liver grafts, including the vascular endothelium and bile ducts. Our results support an association between CMV infection and the immunological mechanisms of rejection, as well as the role of CMV in the development of bile duct damage in liver allografts. (HEPATOLOGY 1998;27;996-1002.)Cytomegalovirus (CMV) infection is a major source of morbidity and mortality in transplant recipients and other immunocompromised patients. The incidence of CMV infection among liver transplant recipients is high, and 40% to 70% of these patients develop a symptomatic CMV disease. 1-4 A variety of clinical manifestations of CMV infection, such as fever, pneumonitis, gastroenteritis, and hepatitis, have been described. The liver is a privileged site for CMV, and the liver graft has been found to be the most commonly affected organ in primary CMV infections. 1 CMV has also been suggested to be linked to organ allograft rejection in both kidney and heart transplantation. [5][6][7] In liver transplantation, the importance of concomitant CMV infection during late acute rejections has been reported. 8 An association between CMV and vanishing bile duct syndrome (VBDS) in hepatic allografts has been found, 9 and persistence of CMV DNA in hepatocytes, 10,11 bile ducts, and vascular structures 11 of the liver has been demonstrated in patients with VBDS. We recently showed that persistent CMV infection in liver allografts is associated with chronic rejection. 11 Va...

Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat

“…Neither was the difference explained by the numbers of macrophages/Kupffer cells in the two groups. We have previously shown that expression of VCAM-1 is up-regulated by CMV in the sinusoidal endothelium in this model [13]. VCAM-1 has been shown to be important for monocyte extravasation [9].…”

“…Concomitant CMV infection led to further increase in COX-2 expression. We have previously shown that CMV increases inflammation and graft damage in this model of acute liver allograft rejection [13]. The pattern of COX-2 induction was different in the CMVinfected and uninfected groups undergoing rejection, although in both groups there was vigorous alloresponse.…”

“…In this rat model of liver transplantation, there are intense signs of acute rejection at 1 week, with portal inflammation and endotheliitis in the graft. In the later phase, at 4 weeks, there is still portal inflammation, but clearly less than at the peak, and the histological pattern is that of necrosis, fibrosis, and bile duct proliferation in response to injury [12], CMV infection significantly increased portal inflammation and bile duct damage in the late phase [13].…”

“…We have previously shown that rat CMV increases portal inflammation and bile duct destruction in rat liver allografts with concomitant rejection [13]. Many of the pro-inflammatory effects of CMV have been shown to be mediated by NF-KB activation [8].…”

Infections After Orthotopic Liver Transplantation

“…86,102 After liver transplantation, CMV increases inflammation in the graft and the expression of class II molecules adhesion molecules critical or T-cell activation. [103][104][105] Despite adequate treatment to resolve viremia, CMV DNA may persist in hepatocytes and bile duct epithelium. 106 As such, successful antiviral treatment of CMV infection does not exclude the persistence of the virus and the risk of chronic rejection.…”